Despite years of development, currently available continuous glucose monitors (CGMs) still lack good accuracy and reliability for short-term and particularly, long-term use in diabetes management. While insulin pumps work well, CGM remains the single largest hurdle to closing the loop of an artificial pancreas. The main obstacles to achieving a long-term, accurate CGM are instabilities in the sensing chemistry and the body's immune response against the sensor - specifically the foreign body response (FBR) - leading to biofouling, inflammation, avascular fibrosis and sensing chemistry degradation. Additionally, current CGM systems in the market and under development are either bulky percutaneous probes or implantable devices encased in hard metals or plastics that become surrounded by an avascular tissue capsule over time or are taken up by immune cells (if nano-sized). In this Phase I SBIR, we propose to demonstrate the feasibility of a minimally invasive, long-term, non-enzymatic glucose sensor produced using our novel, tissue-integrating smart hydrogels that become part of the tissue they are sensing to overcome the FBR. The near infra-red (NIR) fluorescence of the smart hydrogel modulates based on the glucose concentration and is detected non- invasively through the skin. The long-term, vascularizing nature of these hydrogel sensors provides exquisite capillary proximity to more than 1000 times greater sensor surface area compared to traditional electrochemical sensors, thereby overcoming the FBR and enhancing accuracy and longevity of glucose detection. The proposed CGM system contains no implanted electronics or hardware in the body. An external optical reader monitors interstitial glucose transdermally based on changes in the NIR optical signal. The optical reader takes the form of a thin-film micro-optical skin patch or a hand-held wand. PROFUSA's long- term goal is to develop a self-calibrating, injectable, soft hydrogel CGM with a minimum operational life of 3 months and a longer-term goal of 12 months with sufficient accuracy to enable an artificial pancreas. Moreover, because of the platform-nature of this technology, sensing nanospheres specific to other analytes (e.g. oxygen, lactate) can also be incorporated within the hydrogel matrix. PROFUSA's tissue-integrating sensor platform has been demonstrated to be stable in the body for months to years and to provide superior sensing performance compared to solid, non-tissue integrating sensors. The overall focus in this proposal is to extend the longevity of fluorescent sensing chemistry to match the observed longevity of the in vivo hydrogel platform. Multiple nanotechnology-based stabilizing agents will be employed. We will evaluate the glucose sensor performance with and without platinum nanospheres, catalase and other antioxidants over time. The ultimate objective is to achieve stable sensor response over 3 months with a maximum 5% loss in sensitivity over 1 month in accelerated aging conditions and H2O2 exposure. Refinement of fluorescent tissue-intergrating sensors promises to open a whole new sensing modality for diabetes management and health monitoring.